Abortion is the termination of pregnancy before the 28th gestational week characterized by expulsion of the fetus and the attachment thereof from a pregnant woman. Abortion can be classified into early abortion (before the 12th gestational week) and late abortion (after the 12th gestational week) based upon its occurring time. Abortion can also be classified into spontaneous abortion and artificial abortion based upon the underlying causes. Artificial abortion is the termination of pregnancy induced by surgical operation or a medicament. Spontaneous abortion is the termination of pregnancy due to natural causes, such as some kind of diseases, without artificial interference. Spontaneous abortion includes accidental spontaneous abortion and recurrent spontaneous abortion.
Recurrent spontaneous abortion (RSA) refers to the phenomenon of two or more consecutive abortions characterized by the termination of fetal development in the same gestational week. Recurrent spontaneous abortion affects 2-3% of pregnant women. RSA can be classified into early RSA and late RSA based upon its occurring time. RSA can also be classified into primary RSA and secondary RSA based upon whether there is a normal pregnancy history before the abortion. Clinically, RSAs are divided into early primary RSA, late primary RSA, early secondary RSA and late secondary RSA based upon the two kinds of classification set forth above.
RSAs can be resulted from many causes including abnormity of chromosome, endocrine imbalance, anatomical abnormality of reproduction organs, bacterial infection, viral infection, blood group incompatibility between mother and fetus and environmental pollution, etc. About half of RSAs still have no known cause, and are called unexplained RSAs. Along with the deep understanding of reproductive immunology and the development of immunological assays, immunological factors are thought to be the main cause of unexplained RSAs (Ksouri H, Zitouni M, Achour W, Makni S, Ben Hassen A., Recurrent pregnancy loss related to immune disorders, Ann Med Interne (Paris). 2003 September; 154(4): 233-47.). RSAs associated with immunological factors are called immunological RSAs.
Epidemiological surveys demonstrate that most of the early secondary RSAs are immunological RSAs.
There are several representative hypotheses about the immunological mechanism of RSA, for example: (1) production of the blocking antibodies (BA), such as anti-paternal cytotoxic antibodies (APCA), anti-idiotypic antibodies (Ab2) and mixed lymphocyte reaction blocking antibodies (MLR-Bf) which can inhibit the attack to fetus by maternal immunological system, is inhibited due to the increased sharing of human leukocyte antigens (HLA) between the couple; (2) overactivity of helper T cell 1 (Th1)-derived cytokines and of natural killer cells (NK); (3) abnormal increase of antiphosphokipid antibodies (APA). APA is a group of autoimmune antibodies including anticardiolipin (aCL) antibodies and lupus anticoagulants, etc.
Since the immune recognition mechanism between pregnant woman and fetus has not been fully revealed, the immunological pathogenesis of RSA has not yet been accurately understood. No method of treatment with definite curative effect is available heretofore. Currently, one widely used method for treating immunological RSA is lymphocyte immunotherapy. Immunotherapy of RSA has been applied both in China and other countries since Taylor and Faulk infused to a patient of unexplained RSA a suspension of mixed leukocytes derived from her spouse in 1981 (Gatenby P A, Cameron K, Simes R J. Treatment of recurrent spontaneous abortion by immunization with paternal lymphocytes: results of a controlled trial. Am J Reprod Immunol. 1993 March; 29(2): 88-94.). The immunogen is lymphocytes from the spouse in most cases. The immunotherapy includes isolating lymphocytes from the spouse's venous blood for intracutaneous injection. Alternatively, the condensed leucocytes or whole blood from the spouse can also be intravenously injected. If the live cells are inactivated by 200 rad X-ray radiation prior to intracutaneous injection, the graft-versus-host reaction can be attenuated. Usually, the immunization is performed every 2 weeks for a total of 2 to 4 times before pregnancy and boosted 1 to 3 times after pregnancy. Twenty years after the application of lymphocyte immunotherapy for treating RSA, a great deal of studies from China and other countries have indicated that the therapeutic effect of this therapy is not definite and the therapy has some serious adverse side effects. Most literatures on immunotherapy of RSA from 1981 to 1994.9 had been reviewed. It was found that only one of the six studies that were worthy of analysis demonstrated the effectiveness of the immunotherapy. There was no statistically significant difference between the therapy group and the control group in the other studies (Yan Jianhua and Zhu Xihua, Discussion about the Scientificalness and Research Strategy of Immunotherapy of Recurrent Spontaneous Abortion, KeXue, 1994.6: 59-62). Charles A. Omwandho et al. (Recurrent Pregnancy Losses and the Role of Immunotherapy. Review Article, Arch Gynecol Obstet (2000) 264:3-12) found that though some experimental data seemed to support the effectiveness of lymphocyte immunotherapy, there was no statistical difference between the clinical cure rates of the therapy group and the control group treated only by a non-immunological method such as psychological support and care etc. The immunotherapies using inactivated bacterium or autologous blood irradiated by ultra violet (UV) after in vitro hemolysis obtained as high cure rate as the lymphocyte immunotherapy. These experimental results questioned the effectiveness of the lymphocyte immunotherapy.
In addition, the lymphocyte immunotherapy has some serious adverse side effects such as erythrocyte sensitization, thrombocytopenia and intrauterine growth retardation of fetus etc. Some diseases transmitted by blood such as AIDS may be transferred from one individual to another due to the living cells with intact nuclear materials are used in lymphocyte therapy.
Thus, there is an urgent need for a method for treating immunological RSA with definite therapeutical effect and less side effects.
The inventor of the present invention provides an efficient and safe immunotherapy of RSA based upon the deep research on the pathogenesis of immunological early secondary RSA.